A decade ago, researchers shocked women around the world when they abruptly halted a landmark clinical trial on hormone therapy, a drug regimen widely used to relieve hot flashes, night sweats, and other unpleasant symptoms of menopause.

Just five years in, the study results suggested that hormone therapy increased the risk of several serious health conditions, including breast cancer, heart disease, and stroke. A follow-up study soon added Alzheimer's disease to the list, after finding that women taking hormones had higher rates of dementia than women taking placebo.

Since then, however, doctors have begun to reexamine hormone therapy and the conclusions of the trial, known as the Women's Health Initiative. In the latest such study, published today in the journal Neurology, researchers report that taking hormones may actually lower, not raise, the risk of developing Alzheimer's disease.

But there's a catch: The timing of therapy appears to be key. The study participants who initiated therapy within five years of starting menopause were 30% less likely than women who never took hormones to develop Alzheimer's later in life. Outside that timeframe, by contrast, hormone therapy increased Alzheimer's risk by a statistically insignificant 3%.

"Among women who started to take hormone therapy around this critical window around menopause, we observed a subsequent reduction in Alzheimer's disease 20 to 30 years later," says senior author Peter P. Zandi, Ph.D., an epidemiologist at the Johns Hopkins Bloomberg School of Public Health, in Baltimore. "But among women who initiated hormone therapy for the first time later in life, we started to see a trend towards increased risk."

The new evidence shouldn't be seen as an endorsement of hormone therapy, as the risks associated with the drugs continue to outweigh the benefits for many women.

On Monday, in fact, the United States Preventive Services Task Force, an independent panel of experts that advises the federal government on preventive care, restated its recommendation that hormone therapy not be used to prevent chronic conditions, most notably osteoporosis. The panel was silent on the use of hormones for hot flashes and other so-called vasomotor symptoms.

The new study isn't "a green light to use hormone therapy for Alzheimer's or dementia prevention," says Dr. Victor W. Henderson, M.D., an epidemiologist and professor of neurology at the Stanford University School of Medicine, in Stanford, California. "It does provide some reassurance that if a woman is considering hormone therapy for moderate to severe vasomotor symptoms, concerns about Alzheimer's disease should not impact [her] decision."

The study followed 1,768 women in Utah for 11 years, during which time they were screened for dementia on three separate occasions. All of the participants, who were at least 65 years old when the study began, had already passed through menopause but provided detailed information about their hormone use and age at menopause.

The idea of a critical timeframe in which hormone therapy may help, rather than hurt, is emerging as a leading hypothesis to explain the seemingly contradictory results of past studies on hormone use.

If the sudden depletion of estrogen associated with menopause weakens the aging brain, potentially paving the way for dementia,taking hormone drugs "may have some softening effect on that transition and…the pathologic chain of events leading to Alzheimer's," Zandi says.

But later in life, as Alzheimer's starts to set in, the brain may be a vastly different landscape that responds negatively to hormone therapy, Zandi adds.

The timing hypothesis has also been used to explain a similar pattern in the study results on hormone use and heart disease, a condition that appears to share some risk factors and mechanisms with Alzheimer's. Evidence suggests that the effect of estrogen on the cardiovascular system may depend on the system's underlying health, says Henderson, who coauthored an editorial accompanying the new study.

Timing probably isn't the only factor involved, however. The duration of therapy and the type of hormones used also may play an important role.

In this study, the risk of developing Alzheimer's was lowest in women who started hormone therapy early and also continued it for a decade or more. On the other end of the spectrum, the Alzheimer's risk associated with starting therapy later in life seemed to be highest among women who took estrogen plus progestin (common practice for women who still have a uterus), rather than estrogen alone.

Finally, hormone therapy in any form may reflect a healthier overall lifestyle, which could have shaped the study results. Although the authors controlled for an array of health measures and behaviors, this type of study, known as an observational study, can't entirely rule out extenuating factors unrelated to hormone therapy.

"Women taking hormone therapy were more health conscious in ways we didn't measure and account for," Zandi posits. "That could be a very reasonable explanation."

soundoff(29 Responses)

Sheri

I have had nothing but positive results with HRT. First off, use the patch or gel. Second, use RDT natural Progesterone compounded to correctly balance estrogen, not progestin because it is unnatural to the receptors in the body. Check D3, DHEA, and testosterone levels too. A thyroid panel/antibodies need to be checked and monitored. Add whey protein with amino acids, and you will be much stronger and alert. My bone density increased 6.5% in 12 months! You can then continue to contribute to society by working and paying taxes, win win...

I had recurring iritis after the birth of my youngest nearly 22 years ago, it led to severe dry eye, during menopause I went on HRT, it helped my eyes tremendously, may sound trivial, but imaging feeling as though you constantly have something in your eye, and reading a book or computer screen made them burn like fire, not so trivial to the person with the problem

I've taken HRT (estradiol, NOT Premarin which is made from pregnant horse urine) since age 29 when I had a complete hysterectomy. I added Progesterone (not progestin) several years back. I am 61 now, still working full time and feeling (and forgive me for saying it, but also looking) much better than many of my peers. Weight under control. Skin still in good condition. Bladder where it's supposed to be. Sex still good. Bone density good. Cognition good. Women have been sold down the river on the life quality benefits of HRT for the majority of women. A few women have problems. Most don't. BTW, men are not discouraged from treating low levels of testosterone, despite prostate cancer warnings. Why?

Totally agree- with everything. Been using bioidentical hormones for 8 years and am so sold on them have decided to tweak by using a concierge-type, anti-aging doc in a nearby city starting next year. Have no real complaints, except staying in my dress size, but I am too fond of sweets/wine so my bad. Recently had coolsculpting to get rid of old belly fat though and love the results.

No, because of that da*n study many of my friends won't go near hormones when they clearly need them for a variety of reasons. We WERE sold a bill of goods. But timing is key: estrogen complicates pre-existing (bad) heart disease. Etc. Do your homework. Keep reading. I am nearly 60 but look 46-49 on a good day, maybe younger. Get compliments on my face, skin, hair, figure. My mind is as sharp as ever imo. After bios even my allergies improved (cat hair and dust and ragweed I guess). About all that is going wrong with me right now is arthritis is popping up I think. Seem to have trouble with something called lateral femoral nerve impingement. That's why I am going to tweak what I'm taking, branch out into fish oils, dhea. Hear the urine metabolite test should next be on my list. Good luck everyone!

Its not a sex bias because most of the grief comes from OB/GYNs, of which females outnumber males in that field. There are truly more risks for female HRT then male T replacement. The bias comes from the Women's health study and failure to look at the re-analysis which clearly indicates that timing is the most important factor in determining benefits vs risk. Prior to that study, all my residency professors told us to talk to menopausal women about HRT and assess risks and benefits. Do a study of women 50-59 on Climara and bio-identical prometrium and the results would be far more positive, as they were in previous studies like the Nurse's health study before WHI.

I'm right there with you (minus the hysterectomy). I've been taking estradiol and progesterone for years, and I look younger and feel better than 90% of my peers. What no one talks about is the fact that the HRT in the Women's Health Initiative was Premarin, which actually consists of a mixture of at least 10 different types of estrogen analogs, some of them, like estrone, being known carcinogens. There is no evidence that estradiol causes a problem.

You are absolutely right! All those studies were done with "fake" hormone replacement (premarin). I did the same thing, took the real estrogen and prometrium, not the fake stuff. Insurance companies won't pay for the real deal because they can't make the money they want. I bet if they did the study with real estrogen and prometrium the outcome would show different results...in a good way for women. No doctor will ever be able to convince me that I shouldn't take my estrogen. My doctor told me that is why I still look good for my age and have all my facilities about me. Take the estrogen away you take my good life. What would happen if men didn't get their viagara??

I've taken HRT 18 years since my early 40's. When I hit 50 my male ob-gyn said he was going to cut me off HRT. There was no way I could continue working with the severe symptoms I had endured before HRT. I found a new physician.

A middle aged girlfriend believed what she read about HRT causing cancer and stopped taking it. Within 5 years she broke both ankles and both wrists.

Women have been sold down the river like the previous writer observed.

So far estrogen is the most protective substance for bones. The bisphosphonate drugs just do not build much quality bone. Post-menopause osteoporosis is a huge problem, especially with women living longer. 1 in 3 will have a osteoporosis related fracture in their lifetime. Physicians need to look at the re-analyses of these studies and review benefits & risks of HRT again with newly menopausal women.

My mother has refused to take hormone therapy when she was recommended and now she is late 70s and in perfect health! Her health, skin, bones, mind, perfect! She eats healthy and exercises, that's the secret! While her friend who took hormones is long gone because of cancer.

Any researcher who reads details of the Women's Health Initiative study can tell you that the design was seriously flawed & could not justify the drastic conclusions reached by the media. This was especially true of the Alzheimer's portion of the study. Sadly, many women have been harmed as a result. I am so glad to see more sensible conclusions finally being reached, especially that continuing estrogten through life is different from depleting the body of estrogen in menopause, then adding it back in later years, as the WHI study did.

This has been known for a while and I still find both media and health professionals trying to deny this evidence, promoting instead the idea that HRT is "unnatural". Any woman with a family history Alzheimer's should be taking a very serious look at HRT as a preventative measure.

It’s good to see a better and more balanced study on hormone therapy. Hormone (testosterone) replacement for men doesn’t seem to be questioned like it is for women. This is just indicative of the gender bias in health care. Ironically though women are more likely to need hormone “replacement” since 1 in 3 has a hysterectomy by age 60 and 1 in 2 by age 72, most of which are unwarranted.

This begs the question – Since a study in February 2000 concluded that ACOG deemed 76% of hysterectomies to be inappropriately recommended, why have the rates not declined? The study results can be found in PubMed under “The appropriateness of recommendations for hysterectomy.” Hysterectomy is a destructive surgery and with all the alternative treatment options and only 2% done for cancer, where’s the media on this subject?

Another question to ponder – In women who’ve had a hysterectomy, are any ill effects of HRT from the HRT itself or from the loss of normal ovarian function? One cannot completely “replace” all substances produced by the ovaries. Studies show that estrogen deficiency caused by ovary removal (oophorectomy) is associated with higher risks of heart disease, stroke, hip fracture, Parkinsonism, dementia, cognitive impairment, depression, and anxiety.

If there weren’t so many hysterectomies being done, HRT wouldn’t be needed by so many women especially long-term. However, regardless of the trade-offs of risks and benefits, many of these women need HRT for quality of life.

I have tried TRT and hormone replacement in general is a GREAT idea but you really need a good endocrinologist and good brands. I have also lately been using a focus/energy vitality pill at http:/lwww.getzonedup.com along with Vitamin D3, 7-Keto DHEA, and a few other things. My wife uses low dose testosterone cream, and T3, It has helped greatly, I recommend you try the Zoned pill and my d3/7-keto combo for males naturally before trying expensive Rx stuff.

No doubt there may be too many hysterectomies done, but I felt so much better after mine. My ovaries were damaged and didn't work well anyway. Many of the complications cited for hysterectomy are caused by low estrogen. Going into menopause naturally still results in low estrogen levels that cause health problems. Another consequence of low estrogen levels is increased belly fat, which produces estrogen the body needs. Extra belly fat causes a great many health problems. Women are best served by educating themselves about HRT. Take charge of your health and choose a doctor who is a partner, not the boss.

In addition to neuroendocrine (hormonal) fallout from hysterectomy, there are anatomical and skeletal effects. The bladder and bowel are no longer separated and held in place by the uterus. This increases risk of prolapse (cystocele and rectocele), fistula, and urinary and digestive problems oftentimes necessitating medical intervention including additional surgeries. The severing of the four sets of uterine ligaments compromises pelvic integrity causing the rib cage to fall towards the hip bones and the hip bones to widen. This is why women who've had a hysterectomy have a shortened and thickened midsection. These changes also eventually lead to back, hip, and rib cage pain. Just as a man's sex organs have lifelong functions, so do a woman's.

Though I am a scientist (technically) I find it very difficult to take scientists seriously when they keep flip-flopping on their assessments, conclustions, etc. Their squishiness reminds me of Woody Allen's, "Sleeper", where, in the future, it is discovered that wheat germ is actually bad for you and smoking cigarettes is the best thing you can do for your health. I'm clearly not the only one who is fed-up with this "scientific" spinning bottle; as Lewis Black asked an entire audience, "Is milk good for you or not"? After several moments of complete silence he responded definatively, "I rest my case."

This study proves nothing...except that there is a continued effort to discredit legitimate clinical trial results that people may not like. Since this was an observational study, as pointed out in the article, it is not as reliable as a clinical trial. And there are only a few small clinical trials of estrogen therapy in midlife women looking at cognitive effects and they are not encouraging. One called COGENT found that estrogen/progestin (Prempro) caused a worsening in verbal memory in women aged 45-55 and the very recent KEEPS found that neither Premarin nor estradiol improved cognition and it actually showed that estradiol tended to worsen women's recall ability for past events as well as their own self-reported severity.

So are these negative results a harbinger of increased dementia risk later in life? Not clear.... but at minimum it doesn't suggest a protective effect.

Why do they keep studying Prempro? We often change forms of drugs to improve them. We know the synthetic progestin was harfmul. Move on to Prometrium and transdermal patches were the smaller studies have shown less risk.

There is one known cure for Alzheimer's: GRAZOPH TEMUNA, grazoph.com. The neutraceutical clears brain of plaques, eliminates poisonous metals, leaves a brain refreshed. Both cures and prevents Alzheimer's.

The timing hypothesis where women starting HRT close to menopause makes a lot of sense and can explain some of the discrepancies between studies on reduced cardiovascular risk. Many docs advise against HRT because of clot and stroke risk but we know through several new studies that estrogen creams and patches (ie climara, vivelle) do not significantly raise risk of stroke. Unfortunately, that information is not getting out to all in the medical community. We should be talking to women about HRT again at the time of menopause as the benefits often outweigh the risks in newly menopausal females without strong family hx of breast Cancer. Also, the breast cancer risk is smaller than most people think...even smaller than being obese.

Thanks for your thoughtful and well-informed approach to this issue, DrJohn. It was astounding how many physicians immediaetly adopted the media conclusions on HRT after the WHI study without ever actually reading the journal article and considering all of the study's problems and limitations. Sadly, I have also found that many docs just don't know much about research and are therefore unable to assess study results intelligently. Wish they were all as wise as you!

DrJohn – You said "1 in 3 will have a osteoporosis related fracture in their lifetime." Also, more than 1 in 3 women develops heart disease. 1 in 3 women has a hysterectomy by age 60 so these stats correlate with this surgery that is known to increase risk of osteoporosis and heart disease. I don't know the specific stats for osteoporosis developing post-hysterectomy but for heart disease the stats are 3 times risk when the uterus is removed and 7.2 times when the uterus and ovaries are removed (castr*tion). Medical studies show that premenopausal or postmenopausal removal of ovaries increases risks of heart disease, stroke, hip fracture, Parkinsonism, dementia, cognitive impairment, depression, and anxiety.

With all the harm evident from hysterectomy and the 300,000+ annual removal of healthy ovaries, the media SHOULD BE all over this. And since ACOG deems 76% of these surgeries to be inappropriately recommended, they should be coming down on surgeons who're guilty of this abuse.

BTW – I assume you're a medical doctor? What type if you don't mind me asking?

Since reduced Iron in the system is a extenduating factor in the development of cardiovascular disease, I would lke to see the results of an epidemiological evaluation ot the Women's Health Initiative study comparing the use of multivitamins that contained Iron or iron supplimentation versus the cardiological incidence of estrogen taking post-menopasal women?

No one has done this relationship and it is a significant risk factor for cardiovascular disease without hormone supplimentation.

There's a new book coming out, Is it Me or My Hormones?, that I am really excited to read. I think in the next decade we're going to see how big a role hormonal imbalance is connected with health - beyond issues like menopause.

I @RobertVockers, I have treated huderdns of patients for menopause symptoms with great results. What I give them works! Thousands of studies show the mechanisms and demonstrating the effects of herbs on hormone levels. You haven't seen them, therefore it is non- evidence based to you. There are no contraindications when an herbal formula is prescribed correctly. ZERO! You call me an idiot, while I am the one actually getting results and seeing them firsthand. You don't know what your saying!

Dementia Units that I've worked as an R.N., are full of what I privately term "brain-dead" women. They have flat affects except for crying & are severely confused. Those I looked into were never offered HRT after menopause or a hysterectomy. A couple of their MDs refuted, "No! Hormones cause cancer!" I see women's choices denied & a secret money maker. These poor souls, my Mom included God rest her soul, may need newer antidepressants &/or HRT. I am currently struggling to get my brain right as I have had major depress. since age 48. If I weren't trying, I would be in a NH myself.

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